Abstract 15784: Increased 20-HETE Signaling Contributes to Gender- and Mouse Strain-Specific Hypertension in the Setting of Impaired NO-sGC Signaling

Introduction: Hypertension is a multifactorial disease affecting one in three adults in the US. Evidence suggests that dysregulated signaling of the vasodilator nitric oxide (NO) is involved in its pathogenesis. Previously, we reported that mice deficient in the α1 subunit of the NO receptor guanylate cyclase (sGCα1-/- mice), display gender- and strain-specific hypertension: male mice on an Sv129/J (S6) but not a C57BL6/J (B6) background are hypertensive. Methods and Results: Via linkage analysis, we identified a quantitative trait locus (QTL) associated with elevated blood pressure in male sGCα1-/-S6 mice. This QTL encompasses the gene encoding CYP4a12a, a predominant synthase of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE) in murine kidneys. Renal CYP4a12a gene expression, assessed using qRT-PCR, was higher in male WT and sGCα1-/- S6 mice than in female S6 mice or male and female, WT and sGCα1-/- B6 mice. In addition, 20-HETE levels, measured via liquid chromatography-tandem mass spectr...